An animal's immune system is comprised of numerous elements that act separately and/or in concert to counteract, to eliminate, or to neutralize substances that are recognized by that system as foreign to the animal host. Generally, but not necessarily, the substance recognized as foreign by the immune system has its origin exogenous to the host. Exemplary of such exogenous substances are infectious bacteria and the by-products of their cellular activity, virus particles and their proteins, proteins injected by insect stings, and the like. In autoimmune diseases, such as rheumatoid arthritis, the host's immune system perceives host-made proteins or self-made proteins as foreign.
The principal effectors of the immune system are the leukocytes, which include lymphocytes of thymic origin (T cells), lymphocytes produced in bone marrow (B cells), neutrophils which, inter alia, produce enzymes that make oxidizing agents such as hydrogen peroxide that have cytotoxic effects upon bacteria, and macrophages, which present the foreign substance or immunogen (antigen) to the T cells and B cells, as well as produce a protein designated interleuken-1 that assists T cell transformation into T helper cells and B cell and T cell proliferation. Complement, which is a complex mixture of proteins that acts in an ordered, cascading manner upon the foreign substance, also plays a major role in immune responses.
B cells can be distinguished from T cells, inter alia, by the presence of monomeric immunoglobulins (antibodies) on their surface membranes. Mature B cells secrete antibodies into their environment when properly activated.
There are five known classes of immunoglobulins, identified as IgA, IgD, IgE, IgG, and IgM on the basis of five antigenically different heavy chain proteins that make up a portion of the immunoglobulin molecule. B cells also bear non-immunoglobulin cell markers, including a complement receptor (CR), a receptor for the Fc portion of immunoglobulin (FcR), I-region associated antigens (Ia), and a set of differentiation antigens (Lyb 1-7) that are identified by antisera and other means are correlated with various aspects of B cell maturation and activation. These markers are useful in phenotypically identifying B cells and B cell subpopulations.
While the immunoglobulins act upon the foreign substances, or antigen, the T cells, and particularly helper T cells, are believed necessary to stimulate B cells to divide and to differentiate into antibody secreting cells for humoral immunity. Suppressor T cells contribute to the regulation of humoral immunity, while cytotoxic T cells and T cell mediators of delayed-type hypersensitivity are the principal effectors of cell-mediated immunity.
Murine T cells bear surface antigens designated Lyt 1, 2, and 3 as well as L3T4 that are related to T cell functions. Helper T cell precursors are of the Lyt 1.sup.+, 2.sup.-,3.sup.- L3T4.sup.4 phenotype. These cells normally participate in the activation and regulation of B cells.
Helper T cells are known to assist in activation and differentiation of immunoglobulin-secreting B cells after a first message is received by the B cells from the activating immunogenic (antigenic) agent usually presented to it after processing by an antigen-presenting cell. However, the mode by which the T cells provide help for activation and differentiation of the B cells is a matter of controversy.
The immune response exhibited by animal cells can be modified by artificial suppression (immunosuppression) or enhancement (immunopotentiation). Artifically induced immunosuppression can be achieved by six general methods: (1) administration of a suppressive dose of antigen, (2) administration of specific antisera or antibodies, (3) use of other biologic reagents such as antilymphocyte antisera, (4) use of drugs or hormones, (5) radiation, and (6) surgical removal of lymphoid tissue. Immunopotentiation can be achieved by administration of an agent effecting (1) an increase in the rate at which the immune response develops, (2) an increase in the intensity or level of the response, (3) a prolongation of the response, or (4) the development of a response to an otherwise non-immunogenic substance.
The agents that are known to enhance immune responses are generally termed adjuvants and can be placed into two general categories: (1) those providing general potentiation; i.e., substances that enhance cellular and/or humoral immune responses for a wide variety of antigens, and (2) those providing specific potentiation; i.e., substances that enhance specific responses only to certain antigens.
Substances that can act as adjuvants can be grouped into the following categories: (1) water and oil emulsions, e.g., Freund's adjuvant, (2) synthetic polynucleotides and other polyanions, (3) hormones, drugs and cyclic nucleotides, (4) microbial products, e.g., endotoxins, (5) lymphokines and monokines such as the interleukins, and (6) synthetic peptides, e.g., bestatin and tuftsin.
A substance capable of specifically potentiating the immune response is transfer factor, a dialyzable leukocyte extract (DLE) obtained from human peripheral leukocytes. It has been reported that the transfer factor exhibits some effectiveness in patients with immunodeficiencies and possible effectiveness in cancer patients and in patients with limited immunodeficiencies. However, the efficacy of this agent is highly controversial, and much remains to be learned about it.
In some diseases and physiological conditions such as X chromosome-linked agammaglobulinemias, senescence and drug-induced-immunosuppression, B cell activation and differentiation is lacking or exists only at a reduced level, thereby lessening the immune response capabilities of the host. These diseases and conditions are representative of immunosuppressed states. Here, enhanced B cell activation and differentiation, if it can be effected, tends to beneficially lessen the immunological deficits that can manifest themselves as disease and/or improve the patient's condition.
An immunopotentiated state can be illustrated by the bodily condition after vaccination. Here, the immune response is first enhanced due to a primary response to the vaccine's immunogen, and usually can be beneficially enhanced still further by a "booster" injection of the immunogen or vaccine, administered later to provide an improved degree and/or duration of immunity.
Lymphokines and monokines are immunopotentiating proteins produced by lymphocytes and cells of the monocyte-macrophage lineage, respectively. One monokine, interleukin-1, is produced by macrophages when they are stimulated by a mitogen or antigen. Interleukin-1 is usually required for producing a primary antigenic response.
Interleukin-1 assists in the production of interleukin-2 by T cells. Interleukin-2 is a growth factor for T cells and assists in the transformation of helper T cells. Thus, induction of interleukin-1 production or of a protein-responsive activity or T cells similar to that produced by interleukin-1 would be beneficial in enhancing immune responses, particularly where macrophages are absent or where their production of monokines is deficient.
Co-assigned U.S. Pat. No. 4,539,205 to Goodman and Weigle describes modulation of animal cellular responses with 8-substituted guanine derivatives bonded 9-1' to an aldose having 5 or 6 carbon atoms in the aldose chain (ring). The cellular modulations described in that patent relate mostly to immunomodulation such as adjuvanticity in producing primary and secondary immune responses. Activity against certain neoplastic conditions is also disclosed as are T cell-replacing activity, an IL-1 like activity on thymocytes, and induction of the release of lysosomal enzymes from neutrophils. The 8-substituents in those molecules have electron withdrawing inductive effects relative to hydrogen. Thus, halo, mercapto or its thioxo tautomer, acyl mercapto, alkyl sulfido, nitro, cyano, keto, halomethyl and methyleneoxy alkyl and the like were disclosed as useful, while electron donating substituents such as an amino group were found to be inactive.
In addition, co-assigned, co-pending U.S. patent application Ser. No. 546,679 and its corresponding published European patent application No. 83306791.1 further discloses the use of derivatives of 8-hydroxyguanine (8-oxoguanine), 7-methyl-8-oxoguanine and 7-methyl-8-thioxo-guanine in modulating animal cellular responses. Further results using guanine derivatives disclosed in U.S. Pat. No. 4,539,205 are also disclosed as are similar results using guanine derivatives disclosed for the first time in that application.
U.S. Pat. No. 3,798,210 to Pfleiderer describes the synthesis of 8-(1'-glycosidyl)pteridines, including isoxanthopterin derivatives. That patent teaches the use of its compounds as the active pharmaceutical agents against specific pathogens such as malaria and tubercle bacilli, pathogenic fungi, gram-positive and gram-negative bacteria, and primarily against viruses such as herpes virus and influenza virus. Some of the compounds of the Pfleiderer patent are also useful herein, but not as antibiotics as is taught in Pfleiderer. This use is described hereinafter.